16, 17-acetals and ketals of 6-halo-16, 17-dihydroxy steroids of the pregnane seriesand intermediates therefor



United States Patent 16,17-ACETALS AND KETALS 0F 6-HALO-16,17-DI- HYDROXY STEROIDS OF THE PREGNANE SERIES AND INTERMEDIATES THEREFGR Josef Fried, Princeton, N..I., assignor, by mesne assignments, to- Pharmaceutical Research Products, Inc., Abingdon, Va., a corporation of Virginia No Drawing. Filed Aug. 6, 1958, Ser. No. 753,401

12 Claims. (CI. 260-43955) This invention relates to, and has for its object the provisions of, a method of preparing physiologically active steroids, and to the physiologically active steroids produced thereby.

The steroids of this invention include the 16u,17u-acetal and ketal derivatives of l6a,17a-dihydroxy steroids and ketones or aldehydes, and more particularly steroids of the general formula wherein the 1,2-position is saturated or double-bonded; R is hydrogen, R is fl-hydroxy or together R and R is keto; X is hydrogen, halogen (i.e. fiuoro, chloro, brorno or iodo), hydroxy, lower alkyl, or lower alkoxy; X is hydrogen or lower alkyl; Y is hydrogen or methyl; Y is tab "ice

wherein the 1;2-position is saturated or double-bonded; R, R, X, X, Y and Y are as hereinbefore defined; and Z is hydrogen or hydroxy, with an aldehyde'or ketone of the formula:

wherein P and Q are as hereinbefore defined, and recovering the resultant acetal or ketal derivative. The reaction is preferably carried out by treating a suspension or solution of the steroid in the aldehyde or ketone with or without an inert organic solvent (e.g. dioxane) with an acid catalyst (eg perchloric acid, p-toluenesulfonic acid and hydrochloric acid), neutralizing the acid and recovering the acetal or ketal derivative formed.

Among the suitable starting steroids utilizable in the process of this invention may be mentioned,

Ga-halo-l6a-hydroxyhydrocortisone (e.g.6oc-fiu0r0-16ochydroxyhydrocortisone) Got-halo-l6a-hydroxycortisone, Got-halo-16a-hydroxyprednisolone, 6whale-16a-hydroxyprednisone, 6a,9adihalo-16ahydroxyhydrocortisone (e.-g. 6a,9oz-- difluoro-16a-hydr0xyhydrocortisone) 6a,9a-dihalo-16a-hydroxycortisone, :,9cc-dil1fllO-1fia-hYdI'OXYPICdniSOlOHE, (e.g. 6a,9ot-

difluoro-16u-hydroxyprednisolone) 6a,9u-dihalo-16a-hydroxyprednisone, Za-methyl-fia-fluoro-l6a-hydroxyhydrocortisone, Za-mBthYl-6wflUOIO-l6oz-l'lYdf0XYCO1tiSOI16, 6a-fiuoro-l 1,8,16a,17a-trihydroxyprogesterone, 6a-liuoro-1 1-keto-16a,l7 u-dihydroxyprogesterone, a-fiuoro-l 13,16a.,l7ot-trihydroXy-l-dehydroprogesterone, 6a-fiuoro-1 1-keto-16u,17u-dihydroXyl-dehydroprogesterone, 6a,9adihalo-l1,8,l6a,l7a-trihydroxyprogesterone (e.g. 6a,

9a-difluoro-1 15,16m,17oz-trihydroxyprogesterone) 604,9cL-dihfllO-l 113,1 6oz,17ot-t1ihYdl0XY-l-dfihYdIOPIOgEStCI- one (cg. 6u,9a-difluoro-l1,8,16u,17oc-trihydroxy-1-de hydroprogesterone), 6C.-h3.lO-9OL-(1OWB1 alkyl)-16a-hydroxyhydrocortisone (e.g.

60t-fil1OI0-9DL-m6thyl- 1 6a-hydroxyhydrocortisone) Goa-hilO-9ot-(1OW6I alkyl)-16a-hydroXycortisone, 6oz-h3lO-9a-(1OW6I alkyl)-l6a-hydroxyprednisolone, 6a-halo-9a-(lower alkyl)-l6u-hydroxyprednisone, 6a,9a-dihalo- 1 2a- (lower alkyl -l6u-hydroxyhydrocortisone (e.g. 6a,9a-difiuoro-Bot-methyl-l6a-hydroxyhydrocortisone), 6a,9a-dihalo-l2a- (lower alkyl)-161x-hydr0xycortisone, 60:,9ot-dil1fllO-l2oz-(1OWBI' alkyl)-l6a-hydroxyprednisolone (e.g. 6a-chloro-9u-fiuoro-12u-methyl-16m-hydroxyprednisolone), and 6a,9a-dihalo-l2a-(lower alkyl)-16a-hydroxyprednisone.

Particularly preferred steroid reactants are those wherein the 1,2-position is either saturated or double-bonded, R is hydrogen, R is B-hydroxyor together R and R is keto;

; X is hydrogen, chlorine or fluorine;'Y is hydrogen; Y is fluoro; and Z is hydrogen or hydroxy.

In those cases where the starting steroid reactants'are new compounds, they can be prepared from the corresponding 16-desoxy derivative by subjecting the latter to the oxygenating action of a microorganism such as Streptomyces roseochromogenus in accordance wit-h the method described in the US. application of Josef Fried et al., Serial No. 739,943, filed June 4, 1958, now Patent No. 2,855,343.

Suitable aldehyde and ketone reactants include aldehydes such as paraldehyde, propanal, chloral hydrate, trifluonoacetalde'hy-de hemiacetal, heptafluorobutanal ethyl hemiacetal and hexanal; di(lower alkyl)l etones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methyliso butylketone; monoand vdicycloalkyl ketones, such as cyclohexylmethyl ketone and dicyclopro- .pyl ketone; cycloalkanones, such as cyclobutanone, cyclopentanone, cycl-ohex-anone, suberone, and cyclodexa none; monocyclic aromatic aldehydes such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and pafluorobenzaldehyde), lower alkoxy benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy) benza'ldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxy-benzaldehydes (e.g. resorcylaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl) benzaldehydes (e.g. o,p-dim'ethyl'benzaldehyde), nitrobenzaldehydes, a'cylami-dobenzaldehydes (e.g. N-acetylanthranilaldehyde), and cy-anobenzaldehydes; monocyclic aromatic lower 'alkanals, such as phenyl-acetaldehyde, a-phenylpropionaldehyde, fl-phenylpropionaldehyde, 'y-phenyb butyraldehyde, and arom-atically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acyl-amide and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, f urfural, thiophene carbon-als, andhalo, lower alkoxy, hydroxy, lower alkyl, nitno, and cyano derivatives thereof; and monocyclic heterocyclic lower alkanals, acetophenone, propiophenone, hu-tyrophenone, valero phenone, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone), (lower alkoxy)phenyl lower alkyl ketones (e.g. panisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl).pheny1 lower alkyl ketones' (e.g. methyl p-tolyl ketone), di(lower .alkyl)-phenyl lower alkyl ketones (o,p-xylyl methyl .ketone), nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone), acylamidophenyllower alkyl ketones (e.g. acetylanilines), and cyauophenyl lower alkyl ketones; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, .acylamido and cyano derivatives there- :of; monocyclic aromatic lower al-kanones, such as l-phenyl 3 -.butanone and 1 phenyl 4 pentanone, and aromatically substituted derivatives thereof; monocyclic' heterocyclic ketones, such as Z-acetybfuran, 2-benzoylfuran, and 2-acetyl-thiophene; mon-ocyclic heterocyclic lower 'a-lkanones; and m o-nocyclic h-eterocyclic ketones, such as allox an. g g

If a 24l-ester' derivative is the desired product, the corresponding 2l-hydroxy steroid can be acylated in the usual manner. Thus, to prepare the preferred 21-acyloxy derivatives wherein the acyl radical corresponds to the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, either the acyl halide or acid anhydride of a lower alkanoic acid (e.g. acetic, propionic and tert-butyric acid), a monocyclic aryl carboxylic acid (e.g. benzoic and toluic acid), a monocyclic aryl lower alkanoic acid (e.g. phenacetic and ,B-phenylpropionic acid), a lower alkanoic acid, a cycloalkanecanboxylic acid, or a 'cycloalkenecarboxylic acid is employed as a reactant. I g

All of the compounds of this invention are physiologig cally-active subslanCi s which possess glucocorticoid and 75 in monocyclic aromatic ketones, such as 0 anti-inflammatory activity and hence can be used in lieu of known glucocorticoids such as hydrocortisone and cortisone in the treatment of rheumatoid arthritis, in the treatment of dermatoses, for which purpose they can be administered in the same manenr as hydr-ocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 160C,1 7a isopropylidene 6a-flu0ro-triamcinolone (16a,

17a isopropylidene 600,90: difluoro A pregnadiene-11fl,16a,1 711,21 -tetr l-3,20-di0ne) To a suspension of 500 mg. of 6a-fluoro43riamcinolone in ml. of acetone is added 0.05 ml. of 72% perchloric acid and the mixture agitated at room temperature for three hours; During this period the crystals gradually dissolve and the clear solution is neutralized with dilute bicarbonate and the acetone removed in vacuo. The resulting crystalline suspension is filtered andthe crystals washed with water. The dried material is recrystallized from alcohol to give the pure acetonide.

I EXAMPLE 2 To a suspension of 500 mg. of 6aafluoro-triamcinolon-e in 75 ml. of acetone i-s'a-dded 0.05 ml. of concentrated hydrochloric acid and the mixture is stirred at room temperature for 6 hours. It is then treated as described in Example 1 and gives pure 6u-fluoro-triamcinolone acetonide.

EXAMPLE 3 A suspension containing mg. of 6a-fiuoro-triamcinolone and 50 mg. of p-toluene-sulfonic acid in 15 ml. of acetone is stirred for 21 hours at room temperature. The clear solution is worked up as described in Example 1 to give the pure acetonide.

EXAMPLE 4 1 6'a,17a-is0propylidene 6m-flu0r0-triamcinol0ne 21 acetate A solution of 50 mg. of 6a-fluoro-triamcinolone acetonide in 1 m1. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane gives the pure acetate. i

EXAMPLE 5 1606,] 70c- 2 '-butylidene) 6 oz fluoro-triamcinolone To a suspension of 100mg. of 6a-fluoro-triamcinolone 60} in 15' ml. of methylethylketone is added 0.05 ml. of

72% perchloric acid, and the mixture stirred at room temperature for two hours. The resulting solution is neutralized with sodium bicarbonate solution and after addition of water the methylethylketone is evaporated in 65] vacuo. The resulting crystals are filtered, washed with water and dried in vacuo. .Recrystallization from acetone-hexane gives the pure isobutylidene derivative.

' EXAMPLE 6 To a suspension of 100 mg. of 6a-fiuoro-triamcinolone 15 ml. of methylisobutylketone is added 0.05 ml. 0t

72% perchloric acid. The mixture is stirred at room temperature for 6 hours and the resulting solution ex tracted with dilute sodium bicarbonate solution, Washed with water, the organic phase dried over sodium sulfate and the solvent evaporated in vacuo. Recrystallization of the resulting crystals from acetone-hexane gives the pure isohexylidene derivative.

EXAMPLE 7 A suspension of 200 mg. of 6u-fluoro-triamcinolone in ml. of redistilled cyclohexanone is treated for two hours as described in Example 6.

EXAMPLE 8 1 60:,17 a- (3 -penrylidene)dwfluoro-triamcinolone A suspension of 200 mg. of fia-tiuoro-triamcinolone in ml. of diethylketone is treated for four hours as described in Example 6.

EXAMPLE 9 160;,1 7a-ethylidene 6u-fluoro-triamcirzolone EXAMPLE 10 A suspension of 200 mg. of 6a,9e-difluoro-A -pregnenel15,16 i,17a,21-tetrol-3,20-dione in 30 ml. of acetone is stirred at room temperature with 100 mg. of p-toluenea sulfonic acid monohydrate for 18 hours. The clear solotion is neutralized with sodium bicarbonate solution and the acetone evaporated in vacuo. The resulting crystals are filtered and dried in vacuo. Recrystallization from acetonehexane gives the pure isopropylidene derivative.

Reaction of 6a,9u-difiuoro-A -pregnene-16u,17a,2ltriol-3,11,20-trione with acetone gives the corresponding ll-keto derivative.

EXAMPLE ll 160a,] 7a-cyclohexylidene 6ct-flLtOI'0-16ahydroxyhydrocortisone To a suspension of 100 mg. of u-iinoro-lGu-hydroxyhydrocortisone in 15 ml. of cyclohexanone is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Example 6 and results in the formation of the cyclohexylidene derivative of a-fiuoro-16a-hydroxyhydrocortisone.

, If 6a-fluoro-lfiot-hydroxycortisone is substituted for the 6a-fluoro-16a-hydroxyhydrocortisone in the procedure of Example 11, 16a,l7u-cyclohexy1idene 6a-fluoro16rx-hydroxycort-isone is obtained.

6 EXAMPLE 12 Treatment of Ga-fluoro-I6a-hydroxyprednisolone with acetone in the presence of perchloric acid according to the procedure of Example 1 results in the formation of 16a,17a-isopropylidene Got-fluoro-lot-hydroxyprednisolone.

EXAMPLE 13 a,] 7u-isopropylidene 6a-flu0r0-9ot-mcthyl-16ahydroxyprednisolone (a) PREPARATION OF 541.,6a OXIDO-QfiMETHYIIHYDRO- COR'IISONE 3,20-BIS-ETHYLENE K-ETAL To a solution of 750 mg. of 9a-methylhydrocortisone 3,20-bis-ethylene ketal in 50 ml. of chloroform is added at 0 7.5 m1. of 0.28 N perbenzoic acid. After 18 hours at 4 the mixture is Washed successively with sodium iodide, sodium bicarbonate, dilute sodium sulfite and water, the chloroform solution dried and the solvent removed in vacuo. The residual 5a,6a-epoxide is recrystallized from acetone-hexane.

(b) PREPARATION OF 65 FLUORO 9a. METHYLPREG' NANE 5a,11B,1701,21-TETR0L-3fi0-DIONE 3,213-1551S--E'II.H- YLENE KETLAL To a solution of 500 mg. of 5a,6a-epoXy-9a-methy1- hydrocortisone 3,20-bis-ethylene ketal in 60 ml. of dry benzene and 15 ml. of absolute ether is added 1 ml. of freshly redistilled boron trifiuoride etherate and the solution allowed to remain at room temperature for three hours. After thorough washing with water the organic phase is dried over sodium sulfate and the solvents removed in vacuo. Recrystallization from acetone-hexane gives the pure fiuorohydrin.

(0) PREPARATIGN 0F GWFLUOROQu-METHYL- HYDROCORT'ISON'E To a solution of 500 mg. of 6fi-fluoro-9a-methylpregnane 5a,11fl,17a,21 tetrol 3,20-dione 3,20-bis-ethylene ketal in 25 ml. of glacial acetic acid is added 3 ml. of concentrated hydrochloric acid, and the resulting solution allowed to remain at room temperature for 18 hours. The mixture is diluted with water and chloroform, the chloroform solution washed with water, dilute sodium bicarbonate and again with Water, dried over sodium sulfate and the solvent evaporated in vacuo. The resulting 6a-fiuoro- 9a-rnethylhydrocortisone is recrystallized from acetonehexane.

(d) PREPARATION OF fiwFLUORO-Sa-METHYB ltia-HYDROXYHYDLROCORTISONE 6a-fluorO-Qa-methylhydrocortisone is fermented with Streptomyces roseochromogenus (Waksrnan No. 3689) following the procedure in Serial No. 739,943. The resultant 6a fiuoro 9a-methyl-l6whydroxyhydrocortisone -is extracted from the filtered broth with methylisobutyl ketone and recovered from the latter solvent by concentratron and filtration of the resulting crystalline material.

(9) PREPARATION OF Ga-FLUORO-StI-METHYL- lfiwHYDROXYPR-IZIDNISOIJONE 6a fiuoro-9a-methyl-16a-hydroxyhydrocortisone is dehydrogenated in a concentration of 200 ,ugjml. with Nocardia auramia following the procedure in the application of Kroll et al., Serial No. 660,748, filed May 22, 1957, now abandoned, thereby yielding 6a-fiuoro-9a-methyb 1G-m-hYdI'OXYPI'CdIliSOlODB.

(f) PREPARATION OF 1fia l'la-IsQPRoPYLlDENE 6a- FLUORO-QMETHYL-16a-HYDROXYPREDNISOLENE Following the procedure of Example 1, but substituting 500 mg. of 6-fluoro-9a-methyl-l6a-hydroxyprednisolone for the 6a-cfluorotriamcinolone in the example, there is obtained 16a,17-isopropylidene 6a-fluoro-9a-methyl-16ahydroxyprednisolone.

EXAMPLE 14 (a) PREPARATION OF 9a-EEUORO-lQa-ME'DHYLHYDRO- CORTISONE -3,20-BIS-ETHYLENE KETAL (1)) PREPARATION OF 160:,1'Ia-ISOPROPYLIDENE 611,90:- DIEL'UORO-12d-METHYL 16a. HY-DROXYHYDROCO'R- IVISONE Following the procedures in steps a, b, c, d, and f of Example 13, but substituting 800 mg. of 9a-fluo'ro-l2ot-methylhydrocortisone 3,20-bis-ethyle'ne ketal for the 9a-methylhydrocortisone 3,20-bis-e thylene ketal in step a, there is obtained l6a,l7a.-isopropylidene 60:,9cc-diflUOIO-l2otmethyl-16a-hydroxyhydrocortisone.

EXAMPLE 15 Following-the procedures in steps e and f of Example 13, but substituting 6a,9u-difluoro-12ot-methyl-16a-hydroxyhydrocortisone for the 6u-fluoro-9a-methyl-16a-hydroxyhydrocortisone in step 2, there is'obtained 16oz,170tisopropylidene 6a,9a difluoro-l2u-fnethyh16a-hydroxyprednisolone;

EXAMPLE 16 160a,] 7a-isopropylidene 6a.,9a-difluor0-A -pregnadien e- 11[3,16oz,17a-tri0l-3,20-di0n (a) PREPARATION oF Sa-F LUO-ROTRIAMCINOLONE ACETONLDE 21-MESYLA'DE To a solution of 1.5 g. of 6u-fluorotriamcinolone acetohide in 15 ml. of anhydrous pyridine is added at 1.5

ml. of methanesulfonyl chloride. After 2.5 hours in the refrigerator ice water is added and the resulting precipitate filtered olf and washed thoroughly with water. The

material is dried and used without further purification in the reduction step. t

(b) PREPARATION on m rm rsoraorrmonnn 6a,9a.

DIFLUORO-A -PREGNADIENE-11B,16a,17a-TRIOL 3,20- mom:

8 Replacing 6a-fiuorotriamcinolone acetonide in Example 16 by 6a.,9a-difluoro-A -pregnene-11,6-16u,17a,21-tetr0l- 3,20-dione acetonide there is obtained the corresponding A -preguene derivative.

EXAMPLE 17 16a,17a-chloral derivative of Ga-fluorotriamcinolone V A suspension of 500 mg. of 6a-fluorotriamcinolone and 4 gm. of chloral hydrate in 20 ml. of dioxane is agitated at room temperature for 24 hours. The mixture is filtered, neutralized with aqueous sodium bicarbonate and extracted with chloroform. The chloroform-dioxane phase is dried over sodium sulfate, the solvent removed in vacuo and the residual chloral derivative crystallized from methanol.

EXAMPLE 18 Following the procedure of Example 1 but replacing the 75 ml. acetone used in that example by a mixture of 10 ml. of dioxane and 10 ml. of 1,1,1-trifluoroacetone there is obtainedthe trifluoroisopropylidene derivative.

EXAMPLE 19 Acetophenonederivative of 6oz-fluoro triamcinolone To a suspension of 4 g. of 6u-fluoro-tria mcinolone in 1 00 ml. of freshly redistilled acetophenone is added 1.0 ml. of 72% perchloric acid and the mixture stirred at room temperature for two hours, during which period all the 6a-fluoro-triamcinolone has dissolved. The solution is neutralized by the addition of '8 ml. of 1.1 N NaOH and of suflicient aqueous bicarbonate to render it neutral. and of sufficient aqueous bicarbonate to render it neutral. acetophenone layer concentrated in high vacuum. The residue it recrystallized from acetone-hexane and the crystals washed well with hexane to remove adhering acetophenone.

- EXAMPLE 20 p-Nitroacetophenone derivative of 6a-flu0r0triamcinolone To asuspension of 200 mg. of 6u-fiuorotriamcinolone in a mixture of 7 ml. of dioxane and 4 grams of p-nitroa-cetophenone is added 0.05 ml. of 72% perchlorie acid and the mixture stirred at room temperature for 3 /2. hours. The mixture is then neutralized with dilute sodium bicarbonate solution and the dioxane and excess p-nitroa-cetophenone removed 'by vacuum steam distillation. The residual aqueous suspension is extracted withchloroform, the chloroform layer Washed with water, dried over sodium sulfate-and the solvent removed in vacuo. The remaining derivative is purified by recrystallization from acetone-hexane.

EXAMPLE 21 A solutionof 50 mg. of the acetophenone derivative of 6a-fluorotriamcinolone in :1 ml. of pyridine 'and l m1. of acetic anhydride is all-owed to stand at room temperature for 18 hours. Removal of-the reagents in vacuo gives a crystalline residue which after crystallization from acetone hexane gives the pure acetate. 7

' Substitution of 6a,'9' x-difluoro-A -pregnadiene-a16a,17a, 21-triol-3,11,20-trione for 6oz-fiuorotriamcinolone'in the procedures of Examples 19 through 21, yield the conesponding l'l-keto derivatives. a I

9 EXAMPLE 22 Acetophenone derivative of 6a,9u-difluoro-Mpregnene' 1 1-5,16a,1 7 :,21 -tetrol-3,20-di0ne A suspension of 200 mg. of 6a,QwdifluOrO-M-pregueHe- *1l5,16a,l7a,21-te-trol-3,20-dione in 3-0 ml. of acetophenone is stirred at room temperature with 100 mg. of otoluenesulfonic acid monhydrate for 18 hours. The clear solution is neutralized with sodium bicarbonate solution and the acetone evaporated in vacuo. The resulting crystals are filtered and dried in vacuo. Recrystallization from acetonehexane gives the pure acetophenone derivative.

Reaction of 6a,9u difiuoro-A -pregnene 16a,l7ot,2ltriol-3,-ll,20-trione with acetophenone gives the corresponding ll-keto derivative.

EXAMPLE 23 Benzaldehyde derivative of 6Z-fll!Or0-'160thydroxyhydrocortisone To a suspension of 100 mg. of oa-fluoro-lou-hydroxyhydrocortisone in 15 ml. of benzaldehyde is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Example 19 and results in the formation of the benzaldehyde derivative of oa-fluoro-l6a-hydroxyhydrocortisone.

If 6a-fluoro-1Ga-hydroxycortisone is substituted for the 6u-fiuoro-l6a-hydroxyl1ydr-ocortisone in the procedure of Example 23 the benzaldehyde derivative of 6rx-fluoro-16ahydroxycortis-one is obtained.

EXAMPLE 24 Furfural derivative of 6a-fluoro-l6a-hydr0xyprednis0l0ne Treatment of 6u-fluoro-l-6a-hydroxyprednisolone with furfural in the presence of perchloric acid according to the procedure of Example 19 results in the formation of the afurf-ural derivative of GOt-flUOI'O-lGOL-hYdlOXYPI'CdIllSOlOIlB.

EXAMPLE 25 16a,17a-all0xan derivative of 6a-fluorotriamcinolone A suspension of 0.5 gm. 60t'flU-0T0tfiamClnOl-0Il6 and 2.5 gm. of alloxan in 20 ml. of dioxane and 0.15 ml. of 72% perchloric acid is agitated at room temperature for 24 hours. The mixture is neutralized with aqueous sodium bicarbonate solution and after the addition of 20 ml. of water extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The residual alloxan derivative is recrystallized from 95% alcohol.

EXAMPLE 26 Dicyclopropyl ketone derivative of 6a-fluorotriamcin0lone Following the procedure of Example 18 but replacing the trifiuoroacetone by dicyclopropyl ketone, there is obtained the dicyclopropyl derivative of 6a-fiuorotriamcinolone.

The steroids of this invention can also be prepared by an alternative method which entails the interaction of a steroid of the general formula 10 wherein R, R, X, X, Y, Z, P and Q are as he'reinbefore defined, with a mono or dihydric alcohol, such as a lower alkanol or a lower alkanediol, such as ethanol, propanol, ethylene glycol or propylene glycol, to yield the corresponding 3-mono-ketal derivative of the formula wherein R, R, X, X, Y, Z, P and Q are as hereinbefore defined, and R" is O-(low-er alkylene)-O- or two lower alkoxy radicals, the ketalization reaction is preferably conducted in the presence of a strong acid such as ptoluenesulfonic acid.

The B-monoketal thus formed is then reacted with a peracid, such as perbenzoic acid or peracetic acid, to yield the 50:,6ot-6P0XY derivative of the formula wherein R, R, R", X, X, Y, Z, P and Q are as hereinbefore defined.

The Mafia-EPOXY derivative is then treated With a hydrogen halide (i.e. hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide) or boron trifiuoride, to yield the corresponding 6,8-halo-5u-hydroxy derivative, the reaction preferably being conducted in the cold (i.e. below room temperature) in an organic solvent for both the steroid and hydrogen halide reactant. If the reaction is carried out employing an aqueous solution of the hydrogen halide,'that is a hydrohalic acid, the 3-ketal group is hydrolized yielding the 3-keto-A -pregnene derivative.

The 5u-hydroxy-6B-halo derivative is then treated with a strong acid, such as hydrochloric acid, in glacial acetic acid, to invert the Gfl-halo group and to dehydrate the steroid (with resulting hydrolysis of the 3-ket-ogroup, if not previously accomplished), thereby yielding the desired 6a-halo-3-keto-A -pregnene derivative.

If a A -pregnadiene is desired as the product, the A -pregnene can then be subjected to microbial l-dehydrogenation by using for example, N ocardia aurantia, as described in the application of Kroll et a1., Serial No. 660,748, filed May 22, 1957, now abandoned. Furthermore, if a 21-ester is desired and a free ZI-hydroxy steroid is used as the reactant, the 21-hydroxy steroid formed can be esterified in the usual manner by treatment with an acyl halide or acid anhydride of a hydrocarbon carboxylic acid of less than ten carbon atoms as described hereinbefore.

1 1 The series of steps inthe alternative process of this in vention can be represented by the following equations:

form is added an ice-cold solution of 0.4 gm. of perbenzoic acid in ml. of chloroform. After 18 hours at The following examples illustrate the alternative process of this invention (all temperatures being'in centigr-ade):

9a-flziara-16a-hydr0xyhydrocortisone acetonide 3-ethylel 1'e ketal --A mixture of 2 gramsof 9u fiudro-l6whydroxyhydrocortisone acetonide, mg. of p-toluenesu'lfonic acid, 16 ml. of ethylene glycol and 60 ml. of benzene is heated at reflux with a Dean-Stark separator for 6 hours. After cooling, the mixture is neutralized with dilute sodium bicarbonate, thelayers are separated and the aqueous phase extracted withchloro'form. The combined benzene and chloroform phases are washed withwater, dried over sodium sulfate and the solvents evaporated in vacuo. The residual ketal after recrystallization from acetone has the following properties: MlP. about 248-250", [x1 +'1.5 (c. 0.5-1 in OHCI I EXAMPLE 28 5 02,,6oc-0Xid0-9ocuoro-l6u-hydroxyhydrocorflsone l i acetonide 3-ethylene ketal To a solution of 1 gm, of 9u-flu'oro- 16u-hydroxyhydrocortisone acetonide 3-ethy-lene ket-al in 20 m1. of chloro- 4 the mixture is washed with dilute sodium bicarbonate and water, dried over sodium sulfate and the solvent evaporated in vacuo. The residual epoxide is crystallized from acetone-hexane.

6p-chl0r0-9a-fluoropregnane-Sa,11[3,16 711,21 -pem0l- 3,20-di0 ne acetonide 3-ethylene ketal To a'solution of 500 mg. of 5a,6woxido-9u-fluoro-16ahydroxyhydrocortisone acetonide 3-ethy1ene ketal in 50 ml. of ice-cold chloroform is added 7 ml. of an ice-cold 0.5 N solution of hydrogen chloride in chloroform. The

' mixture is allowed to remain at 0 for two hours, after which it is Washed with dilute sodium bicarbonate solution and water. .The chloroform solution is dried over sodium sulfate and the solvent evaporated in vacuo. The residual chlorohydrin is used in Example 30 without further purification. f 5

EXAMPLE 30 6a-chl0r0-9a-fluor0-I6u-hydroxyhydrocortisone acemnide To a solution of 500 mg. of the chlordhydrin obtained in Example 29 in 25 ml, of glacial acetic acid is added 3 ml. of concentrated hydrochloric'acid, and the resulting solution allowed to remain at room temperature for 18 hours. The mixture is diluted with water and chloro- 13 form, the chloroform solution washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvent evaporated in vacuo. The resulting 6a-c'hlOIO-9oL-rflUOIO-fl6cc l1ydl'0XyhYdlOCOlilSOHG acetonide is recrystallized from acetone-hexane.

EXAMPLE 31 6a-chl0ro-9a-flu0r0-16ot-hydroxyprednisolone acetonide 6a-Cl1l0lO-9a-flu0l0 16o: hydroxyhydr-ocontisone acetonide is dehydrogenated in a concentration of 200 g/ ml. with Nacardia aurantia, following the procedure in Serial No. 660,748.

Instead of the anhydrous hydrogen chloride used in Example 29 in the opening of the oz,6a-epoX-ide, aqueous hydrochloric acid can be used as follows. In this case the 3-ethylene ketal is hydrolyzed.

EXAMPLE 32 To a solution of 500 mg. of 5u,6a-oxido-9u-fiuoro-l6mhydroxyhydrocortisone acetonide 3-ethylene ketal in ml. of dioxane is added 2 ml. of concentrated hydrochloric acid and the mixture allowed to stand at room temperature for two hours. Chloroform is then added and the mixture extracted with water, dilute sodium bicarbonate and again with water. The chloroforrn dioxane phase is dried over sodium sulfate and the solvent removed in vacuo. The residual chlorohydrin is recrystallized from acetone-hexane,

Replacing the hydrochloric acid in Example 29 or 32 by hydrobromic or hydroi-od-ic acid results in the formation of the corresponding 6;3-bromo and 6fl-iodo-derivatives, which can be converted to 6u-bromo-9 xfluoro-l6- hydroxyhydrocortisone acetonide and 6oz-iOdO-9a fluOrO =1Mbydroxyhydrocortisone acetonide, respectively, by the process of Example 30.

EXAMPLE 3 3 To a solution of 500 mg. of 5u,6ot-oxido-9u-fiuoro-l 60chydroxyhydrocortisone acetonide 3-ethylene ket-al in ml. of chloroform is added 5 ml. of 48% aqueous hydrofiuoric acid and the mixture agitated at room temperature for one hour. Water and chloroform is added and the mixture neutralized with sodium bicarbonate. The chloroform layer is dried over sodium sulfate and the sol- -vent removed in vacuo. The residual 65-tfluorohy-drin is recrystallized from acetone-hexane.

The dfl-fluorohydrin is converted into 6a,9a-difiuoro- 16whydroxyhydrocortisone acetonide as described in Example for the fl-chloro-B-ethylene ketal. Moreover it can be dehydrogenated with N. aurantia as described in Example 31 for the corresponding 6oz-Chl0r0 compound.

EXAMPLE 34 6 ,8,9ozdi fluoro-pregnan 2-5 011,] l [9,1 6 [1,1 70,21 pen-tol- 3,20-dione acetonide .i-ethylene ketal To a solution of 500 mg. of 5u,6a-oxido-9or-tfiuoro-l6ahydroxyhydrocortisone acetonide E-ethylene ketal in 60 ml. of dry benzene and 15 ml. of absolute ether is added 1 ml. of freshly red-istilled boron trifluoride etherate and the solution allowed to remain at room temperature for three hours. After thorough washing with water the organic phase is dried over sodium sulfate and the solvents removed in vacuo, Recrystallization from acetone= hexane gives the pure 6,8 fiuorohydrin.

The processes of Examples 27 through 34 are of general applicability and may be used to convert any of the A -pregnene products disclosed in my applications, Serial Nos. 677,205 and 714,047, filed August 9, 1957, and February 10, 1958, now abandoned, respectively, to their corresponding 51x,6o -oxido derivatives, and thence to the corresponding 6B-hal0-5ot-hydroxy derivatives, from which the desired ot-haio-N -pregnanes are prepared.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of steriods of the formula and the 1,2-dehydro derivatives thereof, wherein R is hydrogen, R i fi-hydroxy and together R and R is keto; X is selected from the group consisting of hydrogen, halogen, and lower alkyl; X is selected from the group consisting of hydrogen and lower alkyl; Y is hydrogen; Y is halogen; P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyciic heterocyclic.

2. l6or,l7a-lower alkylidene 6a,9a-dihalo-l1 8,l6a,l7atrihydroXy-3,ZO-diketo-M-pregnene.

4. 16u,l7a-l0wer haloalkylidene 6a,9at-dihalo-l6a-hydroxyprednisolone, wherein the haloalkylidene radical contains at least two carbon atoms.

5. 5a,6tx oxido 9a-fluoro-l6a-hydroxyhydrocortisone 16a,17a-isopropylidene 3-ethylene ketal.

6. 6fl-chloro-9a-fiuoropregnane-5a,1 1 8,161, 17,21-pentol-3,Z0-dione l6a,l7a-isopropylidene I i-ethylene ketal.

9. A steroid of the formula wherein R is hydrogen, R is fl-hydroxy and together R and R is keto; X is selected from the group consisting of hydrogen and lower alkyl; Y is hydrogen; R is selected from the group consisting of O-(lower alkylene)-O and two lower alkoxy radicals; Z is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical of hydrocarbon carboxylic acid of less than ten carbon atoms; P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined P and Q is selected from the group emes 15 r consisting of cycloalkyl and monocyclic heterocyclic.

10. A steroid of the formula I V r i no Y wherein Y is halogen, R is hydrogen, R is B-hydroxy and together R and R is keto; X is selected from the group consisting of hydrogen and lower alkyl; Y is hydrogen; R" is selected from the group consisting of'-O-(1ower alkylene)-O- and two lower alkoxy radicals; Z is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms; Pand Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, mo-

nocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic. r

11. A steroid of the formula r CHzZ v I?! 41 R -----o P l X \G/ R "0 \Q wherein R is hydrogen, R is B-hydroxy and together R and R is keto; X is selected from the group consisting of l 5 hydrogen and lower alkyl; Y is hydrogen; Y is halogen, Z is selected from the group consisting of hydrogen, hydroxy and the acyloxy of a hydrocarbon carboxylic acid of less than ten carbon atoms; P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alky; and together with the carbon atom to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

12. A member selected from the group consisting of a compound of the formula 2,584,271 2/52 Huffman 260----239.55 2,736,732 2/56 Knowles 260397.3 2,838,496 6/58 Babcock et al. 260239.55 2,838,497 6/58 Spero et a1 260239.55 3,126,375 3/64 Ringold et al. 260239.55

OTHER REFERENCES Cooley, et al.: J. Chem. Soc. (London), December 1955, pages 4373-4377 (pages 4373 and 4376 necessary). Ellis et al.: J. Chem. Soc. (London), December 1955, pages 4383-4388 (pages 4385, 4387, and 438-8 necessary).

LEWISGOTTS, Primary Examiner.

MORRIS LIEBMAN, IRVING MARCUS, B. E. LAN- HAM, LESLIE H. GASTON, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,197,469 July 27, 1965 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patentshould read as corrected below.

Column 1, lines 21 to 34, for that portion of the formula reading C\ read /C\ column 4, line 5, for manenr" read manner line 57, for "6afluoro, in italics, read fiu-flUOIO- in italics; column 7 line 2 for "-HYDROXYPREDNISOL'ENE" read -HYDROXYPRED- NISOLONE column 8, line 39, strike out "and of sufficient aqueous bicarbonate to render it neutral." and insert instead Water and chloroform is then added and the chloroform column 14, line 44, after "16a," inSeTt 17d, column 16, lines 15 to 25, for that portion of the formula reading O\C/CH3 read O\C/CH3 c cH 0 \CH3 Signed and sealed this 15th day of February 1966.

( AL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STERIODS OF THE FORMULA 